Week 12

• Factors that might affect the shape of the concentration-time profile of a drug


  • Route of administration
  • Formulation given
  • Size of the dose given
  • Dosing interval
  • Drug absorption
  • Drug distribution
  • Drug elimination
  • Enterohepatic recycling
  • Sources of pharmacokinetic variability
• The higher the dose given


  The higher the concentration-time profile of the drug
• Most drugs display linear pharmacokinetics, this means that there is a linear relationship between the dose given and the plasma drug concentration achieved
• If you double the dose


  The plasma drug concentration will also double
• If you triple the dose


  The drug plasma concentration will triple
• The more frequently the drug is given at a fixed dose


  The higher the concentration-time profile of the drug as the drug has more time to accumulate in the body
• When a drug is given over a longer dosing interval


  There is greater fluctuation between the peak and the trough drug concentration
• For some drugs a flat pharmacodynamic profile is required, while others need a high peak and low trough level
• The lower the clearance of the drug


  The higher the concentration-time profile of the drug under a given dosing regimen
• B cells


  An important cell within the immune system that develops from stem cells in the bone marrow and can produce large numbers of different antibodies
• Antibodies


  Protective proteins produced by the immune system in response to the presence of a foreign or harmful substance in the body
• Antigens


  A toxin or other foreign or harmful substance which induces an immune response in the body
• Monoclonal antibody


  A single antibody clone that researchers can produce and make copies of in the laboratory that specifically targets a certain antigen, such as one found in cancer cells
• B cells


  • B cells are a key cell within the immune system associated with the immune response
  • Each B cell has individual antibodies on its surface that are specific to a certain antigen target
  • If a B cell meets and antigen that it recognises this activates an immune response
  • Once a B cell encounters an antigen that matches its antibody it becomes activated and undergoes differentiation, becoming either a plasma cell or memory B-cell
  • Plasma cells can produce vast amounts of a specific antibody against the antigen
  • Memory B-cells remain in the circulation for years as part of the immune memory such that if they come that specific antigen again the immune system can be activated quickly
• Antibody


  A large Y-shapes protein that binds to a specific protein called an antigen
• Antibodies


  • Circulate throughout the body until they find and attach to an antigen they recognise
  • Can identify and neutralise proteins that are part of a harmful process within the body (such as toxins, or parts of bacteria or cancer cells)
  • Once an antibody attaches to an antigen it forces other parts of the immune system to destroy the pathogen or abnormal chemicals or cells that are associated with that antigen
• Antigen


  Any substance that causes the immune system to produce antibodies against it
• Types of antigens


  • Pathogens such as a virus
  • Proteins in cancer cells
  • Proteins associated with autoimmune conditions
• Monoclonal antibodies


  Single clones of an individual antibody that targets a specific protein
• Different monoclonal antibodies can be developed that target different proteins in the body
• Each monoclonal antibodies has its own specific target protein
• Development of monoclonal antibodies


  1. Identify the right antigen to attack

  2. Develop the monoclonal antibody in a laboratory

  3. Inject the monoclonal antibody into patients
• Monoclonal antibodies


  • After injection, they travel to their target, activate the immune system and attack that target in the same way the antibodies produced by a persons own B-cells would do
  • They essentially utilise the patients own immune system in a targeted way that is useful for their condition
  • They are used to treat many diseases, including some types of cancer, immunological disorders and infectious disease
• Monoclonal antibody structure


  • Large heterodimeric molecules with a molecular weight of approximately 150kDa
  • Made up of two heavy chains and two light chains that are arranged in a Y shape
  • The bottom of the monoclonal antibody contains the Fc portion, which remains the same amongst all antibodies and is involved in binding to the cells of the immune system to bring about an immune response
  • The top of the Y contains a variable region, which has millions of possible configurations and is designed to match only a single type of antigen
• Movement of monoclonal antibodies across biological membranes


  Convective transport through paracellular pores in vascular endothelial cell membranes
• Convection


  The transport of a substrate by bulk floe, which often involves movement of fluid down a pressure gradient
• Absorption of monoclonal antibodies


  • Limited oral bioavailability, typically <1-2% and are therefore not administered orally
  • Usually administered parenterally, either intravenously, subcutaneously or intramuscularly
  • Subcutaneous and intramuscular absorption is facilitated by the lymphatic system
  • Monoclonal antibody movement through lymphatic channels may be slow and maximum plasma concentrations may not be reaches for several days after giving a single subcutaneous dose
  • Bioavailability after subcutaneous and intramuscular administration is often low to intermediate, compared with small-molecule drugs, which can be explained by the proteolytic degradation of the monoclonal antibody in the interstitial fluid or the lymphatic system
• Distribution of monoclonal antibodies


  • Generally hydrphilic compounds that have difficulty crossing the lipophilic cell membrane
  • Tend to have volumes of distribution that lie between that of the plasma and the extracellular space
  • Often do so slowly because that have difficulty permeating the blood capillary endothelium
  • Interaction between the monoclonal antibody and the antigen can affect monoclonal antibody distribution
  • The location of the target antigen in the body may affect where in the body the monoclonal antibody distributes to
• Renal elimination and metabolism of monoclonal antibodies


  • Due to their high molecular weight, monoclonal antibodies do not undergo significant glomerular filtration or renal elimination or chemical biotransformation via hepatocytes
• Elimination of monoclonal antibodies


  • Mainly catabolised and eliminated from the body through proteolytic degradation that results in smaller peptides and amino acids being generated
  • Half-lives can be quite variable, from two days to several weeks
  • Removal from the circulation can happen through non-specific clearance, target mediated clearance and other mechanisms such as anti-drug antibody-mediated clearance
• Non-specific clearance of monoclonal antibodies


  • Monoclonal antibodies may be removed by nonspecific endocytosis in cells and proteolysis in the reticuloendothelial system
  • Nonspecific endocytosis refers to nonspecific uptake of monoclonal antibody into cells by pinocytosis, and subsequent removal of monoclonal antibody from the circulation
  • One key mediator of this process can be neonatal Fc receptor (FcRn), which protects the internalised antibody from rapid intracellular catabolism
• Target-mediated clearance of monoclonal antibodies


  • Target-mediated drug clearance is a process by which a monoclonal antibody binds with high affinity to its pharmacological target such that this affects its pharmacokinetic characteristics
  • Some monoclonal antibodies can be eliminated by antigen-specific interactions
  • After the monoclonal antibody binds to its specific antigen it may be internalised and catabolised through lysosomal degradation as an antibody-antigen complex
  • The extent to which a monoclonal antibody undergoes target-mediated clearance can depend on the amount of antigen available for the monoclonal antibody to bind to and the size of the dose given
  • In some cases, drug clearance can be greater in patients with greater disease than in patients with less disease
  • The importance of target-mediated clearance as an elimination pathway decreases with saturation of the target. That is, above a saturation dose level, target-mediated clearance becomes of less importance, and clearance of the mAb through non-specific clearance pathway becomes more important
• Concentration-time profiles of monoclonal antibodies


  • Numerous monoclonal antibodies have been reported to have non-linear pharmacokinetics which is believed to be related to clearance if the monoclonal antibody via saturated target-mediated mechanisms
  • At low monoclonal antibody concentrations, top clearance (CL) is relatively unaffected and target-mediated elimination represents the major elimination pathway
  • With increase in monoclonal antibody concentrations, target-mediated elimination pathway starts to become saturated, as a result total CL decreases substantially
  • Target-mediated clearance can lead to the monoclonal antibody displaying non-linear pharmacokinetics at low dose but linear pharmacokinetics at higher doses. This is usually identified and characterised during dose-ranging studies
• ADA-mediated clearance of monoclonal antibodies


  • Administration of monoclonal antibodies to patients may trigger an immune response, leading to the formation of endogenous anti-drug antibodies
  • Immunogenicity refers to the ability of a particular substance, such as a monoclonal antibody, to cause an immune response
  • In certain people some monoclonal antibodies may be recognised by the patients immune system and their immune system may start to produce its own endogenous antibodies against the monoclonal antibody. These endogenous antibodies are called anti-drug antibodies (ADA)
  • Formation of anti-drug antibodies can lead to faster clearance of the monoclonal antibody because binding of the anti-drug antibody to the monoclonal antibody triggers lysosomal degradation of the monoclonal antibody in a similar manner as target-mediated clearance
• Drug interactions with monoclonal antibodies


  • Since the metabolism, distribution and elimination of monoclonal antibodies are not mediated by CYP450 or drug transporters, monoclonal antibodies are not expected to compete directly with small drug molecules
  • This means its unlikely the monoclonal antibodies cause drug interactions
  • One exception to this is monoclonal antibodies ca alter cytokine levels in circulation
  • Certain cytokines can alter the expression of CYP450 enzymes which can in affect the metabolism of drugs that are substrates for these CYP450 enzymes
  • Certain drugs can potentially also affect target mediate or ADA-mediate clearance of the monoclonal antibody
• Varying the formulation, dose, dose interval and pharmacokinetic parameters of a drug


  Affects the concentration-time profile of the drug
• Steady-state drug concentration during constant intravenous infusion


  Determined by the dose rate and the clearance of the drug
• Time to reach steady-state


  Determined by the half-life of the drug
• Extent of drug accumulation at steady-state compared to the first dose


  Depends on the dosing interval and half-life of the drug
• Oral sustained release formulations


  • Appropriate for drugs with short half-lives and narrow therapeutic indexes